Project Summary/Abstract Pyrrolidinones, piperidinones, indolines, and their derivatives are heterocycles found in a wide variety of biologically active molecules and natural products. As privileged scaffolds for the discovery of new medicines, these heterocycles have attracted extensive research efforts from synthetic chemists. While substantial progress has been made in the synthesis and application of sp2-hybridized heterocyclic frameworks in medicinal chemistry, stereochemically complex N- heterocycles continue to be underutilized in drug discovery. Given the specific importance of chiral N-heterocycles and a growing, broader interest in using 3-dimensional enantioenriched compounds as a strategy to improve clinical success, we will seek to develop new synthetic methods to access these structures in a general, efficient, and stereocontrolled manner. We are interested in applying cascade reactions for this purpose, as the formation of multiple bonds in a single process can impart high levels of efficiency to a synthesis through the generation of molecular complexity from simple starting materials. The overarching aim of this research proposal is to apply hydrogen-bond-donor catalysis as a general strategy for the development of cascade reactions for the synthesis of stereochemically complex N-heterocycles. Specifically, small-molecule chiral thioureas will be used to catalyze tandem processes that generate enantioenriched pyrrolidinone, piperidine/piperidinone, and indoline products. The first aim is to develop a hydrogen-bond-donor mediated, enantioselective Strecker?aza? Sakurai cascade reaction. The reaction would provide a versatile synthetic strategy for the preparation of stereochemically enriched pyrrolidinone, piperidinone, and piperidine heterocycles. The lessons learned from the Strecker-aza-Sakurai cascade reaction would then be used in the second aim to develop a three-component, indole bis-functionalization cascade reaction. Both the Strecker?aza?Sakurai and the three-component, indole cascade reactions will rely on chiral thiourea catalysts to engage starting materials, stabilize transition states selectively through non-covalent interactions, and thereby provide enantioenriched products. Overall, this proposal has three goals: 1) the application of small-molecule chiral thioureas in the development of enantioselective tandem processes 2) the synthesis of an assortment of privileged, biologically active scaffolds, and 3) the study of the reaction mechanisms and elucidation of the origins of enantioinduction. If successful, these studies would provide diverse compound libraries of stereochemically complex N-heterocycles for the treatment of human diseases, and would expand the existing utility of hydrogen-bond-donor catalysts.